contraction is the process which diminishes the size of a full-thickness open wound, and is characterized by the centripetal movement of the whole thickness of surrounding skin. In man, particularly on the extremities and anterior chest wall, contraction may result in significant deformity and loss of function. Because tensions developed during contraction and formation of subcutaneous fibrous tissue may lead to fixed flexion or fixed extension of the joint, avoidance of contraction is particularly important when the wound involves the area over a joint. Thus, wound contraction can be a serious complication of surgery or trauma.
When a full-thickness segment of skin is excised the wound edges immediately retract enlarging the wound. Initially, the wound bed is covered at first with extravasated blood and cell debris. Within 12 to 24 hours the wound bed is invaded by leukocytes, chiefly the polymorphonuclear variety. These are followed by macrophages, whose principal role is to clean up debris preparatory to new tissue formation. Within a few days, capillaries at the base and edges of the wound enlarge and form endothelial buds which rapidly elongate, forming a network of new capillaries in the wound bed. It is these that give healthy granulation tissue a bright red and granular appearance.
Concomitantly with capillary proliferation, fibroblasts invade the wound area, the greatest number usually being seen first at wound margins. Resting fibroblasts are recruited into the wound region where the activated cells proliferate and secrete a new, collagenous matrix that can be seen throughout the wound bed. A subpopulation of wound fibroblasts (often called "myofibroblasts") contain a highly developed actin/myosin cytoskeleton which has been implicated in wound contraction. These elements, associated with mucopolysaccharides and glycoproteins, comprise a wound base over which movement of skin occurs. Five to nine days after the incision, depending on the site, the centripetal movement of the wound margins begins. Thus, fibroblast activities during wound repair and contraction include adhesion, migration, proliferation, matrix synthesis, and contractile force generation.
At the same time the process of epithelization begins. Epithelium provides the barrier to infection and fluid loss. The processes of epithelization and wound contraction are independent; one can occur without the other. Contraction involves movement of the existing dermis at the wound edge, not the formation of new tissue. Usually, wound contraction ceases after epithelization is complete. In some cases, however, e.g. keloids and hypertrophic scars, contraction of the wound bed continues even after complete epithelization has occurred.
The inhibition of wound contraction has been studied. Substances or procedures which interfere with myofibroblast mobilization, migration, adhesion, or multiplication may inhibit wound contraction. For example, high doses of cortisone or related steroids has been shown to delay the development of granulation tissue, depress proliferation of capillaries, suppress fibroblast proliferation, and accordingly, inhibit wound contraction. On the other hand, smaller doses of cortisone have been reported to have no effect on wound contraction. Because steroids given in high doses cause a plurality of untoward effects in patients, steroids are not clinically useful in inhibiting wound contraction.
Cellular poisons, such as cyanide and dinitrophenol, have also been reported to inhibit wound contraction. Likewise, drugs which inhibit smooth muscle contraction have been reported to inhibit wound contraction, for example, colchicine, vinblastine and phenyltoin. These inhibitors of wound contraction (glucocorticosteroids, colchicine, phenyltoin, etc.) have been demonstrated to effective in in vitro wound healing studies, but they have yet to be demonstrated clinically effective.
Physical intervention has also been demonstrated to affect the rate of wound contraction. The influence of dressings on wound contraction seems to be largely mechanical. An adherent dressing, such as untreated gauze, will delay, but not prevent contraction. If a synthetic film such as nylon or cellophane is applied to a wound surface during the lag phase, before active contraction has started, inhibition of contraction will be observed. Likewise, epithelization and fibroblast invasion are prevented.
The effect of skin grafts on contracting wounds has received considerable attention. It has been observed that if a full-thickness skin graft is applied to an excised wound before wound contraction commences, contraction is inhibited. However, significant problems are associated with skin grafting, for example, cost, source of grafting skin, rejection of graft, secondary infection, and all the risks typically associated with any surgical procedure. Accordingly, a new method of inhibiting wound contraction is needed which overcomes the problems associated with the prior art methods.
A method to inhibit wound contraction by using a polypeptide compound offers many advantages over prior methods of treating wound contraction. Among these are: (1) the effective in vivo inhibition of wound contraction in mammals; (2) the prevention of the untoward effects undesired wound contraction in a patient; (3) lower cost treatment of wound contraction; (4) reduced cellular toxicity, and accordingly, a lower incidence of side effects in a patient; (5) a reduced likelihood of secondary infection; and (6) an increased availability of treatment for patients in need thereof.
Fibroblast contraction of collagen gels.sup.1 bears similarities to wound contraction.sup.2,3 and has been used as a model system for studying connective tissue morphogenesis.sup.4,5. During contraction, cells bind to nearby collagen fibrils and exert mechanical forces that are propagated throughout the three-dimensional gel by the interconnected collagen fibril network.sup.6-9. The cell receptors and collagen cell-recognition sequences involved in gel contraction have yet to be identified, but recently several receptors of human osteosarcoma cells were described that recognize the arg-gly-asp sequence in type I collagen coated on tissue culture plastic surfaces.sup.10. As described herein, the peptide gly-arg-gly-glu-ser-pro (GRGESP) inhibits spreading of human fibroblasts inside collagen gels and markedly decreases gel contraction, but this peptide has no effect on cell spreading on collagencoated surfaces. These results suggest that human fibroblasts can interact with different collagen cell recognition sequences depending upon topographical organization of the collagen.